The present invention relates to the field of chemistry and more particularly, to novel crystalline forms of Temozolomide and methods for the preparation thereof. The present invention also relates to the field of pharmacology and more particularly to uses of the novel crystalline forms of Temozolomide in treating medical conditions such as, for example, brain cancer, breast cancer, refractory anaplastic astrocytoma, malignant glioma, glioblastoma multiforme and anaplastic astrocytoma.
Temozolomide is the international non-propriety name used to identify 3-methyl-8-carbamoyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one:

Uses and methods of preparation of Temozolomide are described, for example, in U.S. Pat. No. 5,260,291; U.S. patent application Ser. No. 10/050,768; The Merck Index on CD-ROM, Version 12:3, 1999; Merck & Co. Inc., Whitehouse Station, N.J., USA. Published on CD-ROM by Chapman and Hall/CRC; Stevens et al. J. Med. Chem. 1984, 27, 196-201; Baig and Stevens J. Chem. Soc. Perkin Trans. I 1987, 675-670; J. Chem. Soc., Chem. Commun. 1994, 1687-1688; Clark et al. J. Med. Chem. 1995, 38, 1493-1504; Newlands et al. Cancer Treatment Reviews 1997 23, 35-61; Brown et al. J. Med. Chem. 2002, 45, 5448-5457.
Temozolomide is slightly soluble in water and acidic aqueous solutions (3 mg/ml).
Temozolomide is an antitumor agent indicated for the treatment of patients with malignant glioma such as cancer, brain cancer, breast cancer, refractory anaplastic astrocytoma, malignant glioma, glioblastoma multiforme and anaplastic astrocytoma. Temozolomide is converted in vivo to the cytotoxic monomethyl triazenoimidazole carboxamide.
The presently marketed Temozolomide preparations are hard capsules dosage form containing 5 mg, 20 mg, 100 mg or 250 mg Temozolomide (marketed as Temodar® or Temodal® by Schering Corporation, Kenilworth, N.J., USA).
The crystalline structure of Temozolomide determined by crystallographic methods has not been published in the art. The melting point of Temozolomide has been reported to be 210° C. in Stevens et al. J. Med. Chem. 1984, 27, 196-201 and in U.S. Pat. No. 5,260,291. However, in U.S. Pat. No. 5,260,291 is reported that melting was accompanied by “ . . . effervescence and darkening from 160° C. to 210° C.” indicating that the Temozolomide decomposed rather than melted. It is therefore apparent that melting point is not a property that is useful in characterizing crystals of Temozolomide.
In the Merck index, it is reported that Temozolomide was crystallized from methylene chloride, yielding crystals having a melting point of 212° C.
In U.S. Pat. No. 5,260,291 a number of crystalline forms of Temozolomide were prepared and characterized by infrared spectroscopy in a KBr disk:
a) colorless needles of Temozolomide crystallized from 3:1 v/v mixture of acetone and water (30% by weight water) gave νmax at 3410, 3205, 1758, 1730 and 1687 cm−1;
b) white microcrystals of Temozolomide crystallized from a 1:3 v/v mixture of acetone and water gave νmax at 3430, 3200, 1740 and 1675 cm−1; and
c) a granular solid of Temozolomide crystallized from hot water gave νmax at 3450, 3380, 3200, 1742, 1688 and 1640 cm−1.
Two additional crystalline forms of Temozolomide were reported in U.S. Pat. No. 5,260,291 but were not characterized:
d) a light brown microcrystalline Temozolomide crystallized from a reaction solvent comprising methyl isocyanate by the addition of diethyl ether; and
e) a pale purple solid Temozolomide crystallized from a reaction solvent comprising dichloromethane and methyl isocyanate by the addition of diethyl ether was dissolved in acetonitrile then recovered by evaporation of the solvent. Although infrared spectroscopy was performed, the results were not reported.
Crystalline forms, that include polymorphs and pseudopolymorphs, are distinct solids sharing the same structural formula, yet having different physical properties due to different conformations and/or orientations of the molecule in the unit cell of the crystal. The physical characteristics, such as solubility and stability, of different crystalline forms are often different and are thus exceptionally relevant in the field of pharmacology.
For a general review of crystalline forms (i.e. polymorphs and pseudopolymorphs) and the pharmaceutical applications of crystalline forms see Wall Pharm. Manuf. 1986, 3, 33; Haleblian et al. J. Pharm. Sci. 1969, 58, 911; and Haleblian J. Pharm. Sci., 1975, 64, 1269.
Different crystalline forms of a pharmaceutically useful compound provide opportunities to improve the performance characteristics of a pharmaceutical product. Different crystalline forms enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a desired release profile, solubility characteristics or other desired characteristic. It is well known that new crystalline forms of known useful compounds are of utility.
There is thus a widely recognized need for, and it would be highly advantageous to have new and distinct crystalline forms of Temozolomide.